2. Academic Validation
  3. Using 'biased-privileged' scaffolds to identify lysine methyltransferase inhibitors

Using 'biased-privileged' scaffolds to identify lysine methyltransferase inhibitors

  • Bioorg Med Chem. 2014 Apr 1;22(7):2253-60. doi: 10.1016/j.bmc.2014.02.024.
Sudhir Kashyap 1,  Joel Sandler 2,  Ulf Peters 2,  Eduardo J Martinez 2,  Tarun M Kapoor 3
Affiliations

Affiliations

  • 1 Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA; Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, AP, India. Electronic address: skashyap@iict.res.in.
  • 2 Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA.
  • 3 Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA. Electronic address: kapoor@rockefeller.edu.
PMID: 24650704 DOI: 10.1016/j.bmc.2014.02.024
Abstract

Methylation of histones by lysine methyltransferases (KMTases) plays important roles in regulating chromatin function. It is also now clear that improper KMTases activity is linked to human diseases, such as Cancer. We report an approach that employs drug-like 'privileged' scaffolds biased with motifs present in S-adenosyl methionine, the cofactor used by KMTases, to efficiently generate inhibitors for Set7, a biochemically well-characterized KMTase. Setin-1, the most potent inhibitor of Set7 we have developed also inhibits the KMTase G9a. Together these data suggest that these inhibitors should provide good starting points to generate useful probes for KMTase biology and guide the design of KMTase inhibitors with drug-like properties.

Keywords

Inhibitors; KMTases; Post-translational modifications; SET7; ‘Privileged’ scaffolds.

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